KR20070015566A - NOVEL BIAROMATIC COMPOUNDS WHICH ACTIVATE PPARgamma;-TYPE RECEPTORS, THEIR PROCESS OF PREPARATION AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS - Google Patents

Abstract

The invention relates to novel biaromatic compounds which correspond to the following general formula (I) and to their method of preparation and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, in particular in dermatology as well as in the field of cardiovascular diseases, immune diseases and/or diseases related to the metabolism of lipids, or alternatively in cosmetic compositions. ® KIPO & WIPO 2007

Description

Novel biaromatic compounds activating PAPR-type receptors, methods for their preparation and their use in cosmetic or pharmaceutical compositions {NOVEL BIAROMATIC COMPOUNDS WHICH ACTIVATE PPARγ-TYPE RECEPTORS, THEIR PROCESS OF PREPARATION AND THEIR USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS}

The new and useful invention relates to a new class of diaromatic compounds which are activators of receptors of the peroxysomal proliferative-activating receptor (PPAR-γ) type of γ subtype. The present invention further relates to methods of preparation thereof and to pharmaceutical compositions intended for human or veterinary pharmaceutical use, or alternatively their use in cosmetic compositions.

The activity of PPAR type receptors has been the subject of several studies. For presentation, a publication by J. Invest. Dermatol 111, 1998, p 1116-1121, including Michel Rivier entitled "Differential Expression of Peroxisome Proliferator-Activated Receptor Subtypes During the Differentiation of Human Keratinocytes", may be mentioned. A number of bibliographic references have been listed on PPAR type receptors, see also Timothy M. Willson et al., 2000, 43, 527- entitled " PPARs: From Orphan Receptors to Drug Discovery. &Quot; The report of 550 may also be mentioned.

PPAR receptors activate transcription in the form of heterodimers with retinoid X receptors (known as RXRs) by binding to a DNA sequence element known as a peroxysomal proliferative response element (PPRE).

Three subtypes of human PPARs have been identified and described: PPARα, PPARγ and PPARδ (or NUC1).

PPARα is mainly expressed in the liver, while PPARδ is widely distributed.

PPARγ is the most widely studied of the three subtypes. All references suggest that PPARγ is highly expressed in adipocytes and plays a critical role in regulating the differentiation of adipocytes. It also plays a major role in systemic fat homeostasis.

Additionally, Applicant has already disclosed the use of PPARγ-activating compounds in the preparation of pharmaceutical compositions in patent application FR98 / 02894, which compositions are for the treatment of skin diseases related to the differentiation of epidermal cells.

Applicant also discloses a class of biaromatic compounds which are active agents of the PPARγ receptor in patent FR 2 812 876.

One of the objects of the present invention is to provide a novel class of PPARγ activating compounds which exhibit markedly improved biological activity compared to that of compounds known in the art, and in particular as disclosed in patent FR 2 812 876.

In accordance with the present invention, Applicants disclose a limited group of compounds corresponding to formula (I) shown below, which show surprising biological activity, especially binding affinity for PPARγ receptors, which is significantly increased compared to the compounds of patent FR 2 812 876. Found. This increased binding affinity arises from the surprisingly reduced apparent dissociation constant, as described below.

Accordingly, the present invention provides optical and / or geometric, in all proportions of the possible isomers and possible tautomeric forms, as well as compounds corresponding to formula (I) and compounds of formula (I), and also I) relates to salts of the compounds of:

[In meals:

R1 represents an alkyl group having 1 to 6 carbon atoms, an acetyl group, a methylcyclopropane group, an aralkyl group or an aryl group;

R2 represents an alkyl group having 3 to 8 carbon atoms;

R3 is a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms;

R 4 and R 5, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or a trifluoromethyl radical.

For the compounds of the formula (I) shown above, "geometric isomer" means cis / trans or E / Z isomerism. More particularly, the possible double bonds or bonds present in the various substituents of the compound of formula (I) may be of the E or Z configuration. These pure or non-pure, geometric isomers, alone or in mixtures, form an integral part of the compound of formula (I).

The term “optical isomer” includes all forms of isomers, alone or as a mixture, the presence of which results from one or more axes and / or centers of symmetry in the molecule resulting in rotation of the light rays of polarized light. The term "optical isomer" includes enantiomers and diastereomers, more particularly in pure form or as a mixture.

When the compounds according to the invention are provided in the form of salts, they are preferably of alkali metal salts, in particular sodium salts, or alkaline earth metal salts or organic amine salts, more particularly of amino acids such as arginine or lysine.

According to the invention, the term "alkyl radicals having 1 to 6 carbon atoms" is preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl as any branched, saturated or unsaturated, linear or cyclic alkyl radical selected from n-hexyl, isohexyl, cyclohexyl, ethylenyl, allyl, propenyl, butenyl, pentenyl or hexenyl radicals I understand.

According to the present invention, the term "alkyl radicals having 3 to 8 carbon atoms" is preferably any branched, saturated or unsaturated, linear or cyclic alkyl radical having 3 to 8 carbon atoms and preferably n-propyl, isopropyl, cyclopropyl , n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, allyl, propenyl Is understood to mean a butenyl, pentenyl, hexenyl, heptenyl or octenyl radical.

The term "halogen atom" is preferably understood to mean a fluorine, chlorine or bromine atom.

The term “aralkyl radical” is preferably amino optionally substituted with a halogen atom, a CF ₃ radical, an alkyl radical of 1 to 6 carbon atoms, an alkoxy radical of 1 to 6 carbon atoms, an unprotected or unsubstituted or one or more alkyl of 1 to 6 carbon atoms. It is understood to mean a benzyl, phenethyl or naphth-2-yl-methyl radical, unsubstituted or substituted with one or more radicals selected from a functional or hydroxyl radical, or a carboxyl functional group.

The term "aryl radical" preferably refers to halogen atoms, CF ₃ radicals, alkyl radicals of 1 to 6 carbon atoms, alkoxy radicals of 1 to 6 carbon atoms, nitro functional groups, polyether radicals, aryl radicals, benzoyl radicals, alkyl ester groups, carboxyl groups, Phenyl, biphenyl, cinnamil, which may be mono- or di-substituted with hydroxyl radicals optionally protected with acetyl or benzoyl groups, or amino functional groups optionally protected with acetyl or benzoyl groups or optionally substituted with one or more alkyl of 1 to 6 carbon atoms It is understood to mean naphthyl radicals.

The term "alkoxy radical" preferably means a methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radical, which may optionally be substituted with an alkyl radical having 1 to 6 carbon atoms. It is understood that.

The term "polyether radical" preferably refers to a radical having 1 to 6 carbon atoms to which one or more oxygen atoms are inserted, such as a methoxymethoxy, methoxymethylene, ethoxymethoxy, ethoxymethylene or methoxyethoxymethoxy radical It is understood to mean.

The term "alkyl ester radical" is understood to mean a carboxylate functional group substituted with an alkyl radical having 1 to 6 carbon atoms.

Among the compounds of the formula (I) which fall within the scope of the invention, mention may be made in particular of the following compounds (alone or as mixtures):

1. 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid,

2. 2 (S) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid,

3. 2 (S) -cyclopropylmethoxy-3- [3 '-(3-heptyl-1-methyl-ureido) biphenyl-4-yl] propanoic acid,

4. 2 (S) -propyloxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid,

5. 2 (S) -benzyloxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid,

6. 2 (S) -allyloxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid,

7. 2 (S) -cyclopropylmethoxy-3- [3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid,

8. 3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] -2 (S) -propoxypropanoic acid,

9. 2 (S) -allyloxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid,

10. 2 (S) -benzyloxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid,

11. 2 (S) -methoxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid,

12. 3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] -2 (S) -methoxypropanoic acid,

13. 2 (S) -ethoxy-3- [3 '-(l-methyl-3-propylureido) -biphenyl-4-yl] propanoic acid,

14. 3- [3 '-(3-cyclopropylmethyl-1-methylureido) -biphenyl-4-yl] -2 (S) -ethoxypropanoic acid,

15. 3- [3 '-(3-cyclopentylmethyl-1-methylureido) -biphenyl-4-yl] -2 (S) -ethoxypropanoic acid,

16. 2 (S) -ethoxy-3- [3-fluoro-3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid,

17. 2 (S) -ethoxy-3- [4'-fluoro-3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid,

18. 3- [3,4'-Difluoro-3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] -2 (S) -ethoxypropanoic acid,

19. Methyl 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methyl-ureido) biphenyl-4-yl] propanoate,

20. Methyl 2 (S) -cyclopropylmethoxy-3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] propanoate,

21. 2 (S) -cyclopropylmethoxy-3- [3 '-(3-cyclopropyl-methyl-1-methylureido) biphenyl-4-yl] propanoic acid,

22. 3- {3 '-[3- (2-cyclohexylethyl) -1-methylureido] -biphenyl-4-yl} -2 (S) -ethoxypropanoic acid,

23. 2 (R) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid,

24. 2 (R) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid,

25. 2-ethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid,

26. 2 (R) -allyloxy-3 [3 ′-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid,

27. 3- [3 '-(3-allyl-1-methylureido) biphenyl-4-yl] -2 (S) -ethoxypropanoic acid,

28. Allyl 3- [3 '-(3-allyl-1-methylureido) biphenyl-4-yl] -2 (S) -ethoxypropanoate.

According to the invention, more particularly preferred compounds of compound (I) exhibit one or more of the following properties:

R 1 is selected from alkyl radicals selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl radicals, methyl-cyclopropane groups or benzyl radicals,

R2 represents an alkyl radical selected from n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptyl radicals,

R3 represents a hydrogen atom,

R 4 and / or R 5 are selected from hydrogen or fluorine atoms.

In particular, according to the invention, preference is given to compounds of the formula (I) which exhibit all of the following properties:

R 1 is selected from alkyl radicals selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl radicals, methyl-cyclopropane groups or benzyl radicals,

R2 means an alkyl radical selected from n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptyl radicals,

-R3 means hydrogen atom,

R 4 and / or R 5 are selected from hydrogen or fluorine atoms.

More particularly, the invention provides optical and / or geometric, all ratios of possible isomers, as pure compounds or mixtures of the compounds corresponding to formula (I) or the compounds of formula (I), characterized in that it comprises the following steps, And possible tautomeric forms, or methods of preparing salts of compounds of formula (I):

In the steps described below in connection with FIG . 1 , unless otherwise indicated, the R 1, R 2, R 3, R 4 and R 5 radicals of compounds 1 to 20 are the same as defined for the compound of formula (I).

a) from commercially available 3-bromoaniline optionally substituted with a R5 group, the amine is protected with di (tert-butyl) dicarbonate and then methylated in the presence of sodium hydride, for example with methyl iodide Preparation of a compound of formula 1 by

;

;

b) Preparation of compound 2 , for example by treating compound 1 with an acid such as trifluoroacetic acid:

;

;

c) Preparation of compound 3 by reaction of pinacolborane with compound 2 in the presence of a catalyst such as palladium dichloride diphenylphosphinopropane ferrocene:

;

;

d) commercially available epoxide 4:

Preparation of compound 5 by treating with an aryl courate obtained in the presence of tert-butyllithium and copper cyanide, for example by reaction of an aryl halide such as 1,4-dibromobenzene:

;

;

e) Preparation of compound 6 by reacting compound 5 with an alkyl halide such as ethyl iodide, for example in the presence of silver oxide, in order to avoid racemization problems:

;

;

f) tetrakis (triphenylphosphine) prepared as by the presence of a palladium Suzuki (Suzuki) coupling the compound 3 with compound 6, according to the reaction of the ring type, Compound 7:

;

;

g) Preparation of compound 8 , for example by reaction of an alkyl isocyanate such as heptyl isocyanate with compound 7 :

;

;

h) h1) when R3 is an alkyl radical: by trans-esterification of the alcohol with compound 8 in the presence of an acid such as sulfuric acid,

or

h2) when R 3 is a hydrogen atom: for example by saponification of compound 8 in the presence of a base such as sodium hydroxide,

Preparation of Compound (I) .

According to another advantageous method of synthesizing a compound of formula (I), the step of preparing compound 3 is repeated as defined in parts a) to c), and the step of preparing compound 5 is defined in part d). Repeated as follows, followed by the steps set forth below:

i) Preparation of compound 10 by treatment with compound 5 in the presence of silver oxide, for example with benzyl halide, such as benzyl bromide:

;

;

j) Compounds, for example, by coupling compound 3 with compound 10 by Suzuki-type reaction using a palladium catalyst such as tetrakis (triphenylphosphine) palladium 11 , Manufacturing:

;

;

k) Preparation of Compound 12 by, for example, reacting an alkyl isocyanate such as heptyl isocyanate with compound 11 :

;

;

l) Preparation of Alcohol 13 by Hydrocracking Compound 12 with Hydrogen in the Presence of Palladium-on-Charcoal:

;

;

m) Preparation of compound 8 , for example by reacting compound 13 with an alkyl halide, such as allyl bromide, in the presence of a silver oxide:

;

;

n) preparing compound (I) from compound 8 as defined in step h) (alternatives n1) and n2) are identical to alternatives h1) and h2)).

Compounds of formula (I) are also horned with phosphonate 16 in the presence of a base such as sodium hydride, butyllithium or potassium tert-butoxide, according to the scheme represented by synthetic route 2a in FIG. 2 from aldehyde derivative 15 After a reaction of type (Horner), it can be obtained by hydrogenation in the presence of palladium-on-charcoal and by any enzymatic digestion, for example in the presence of the enzyme proteinase 2 A, by obtaining the (S) enantiomer. . In the above synthesis method, R 1, R 2, R 3, R 4 and R 5 are as defined above.

Compounds of compound (I) may also be used for the preparation of Evans derivatives, for example after the reaction of 4 (S) -benzyloxazolidin-2-one with 2-alkoxyacetate chloride, for example dibutylboron tri These distinct chiral Evans derivatives and aldehyde derivatives in the presence of the plate It can be obtained according to the scheme represented by synthetic route 2b of FIG. 2, which results in derivative 19 by condensation of 15 . Deoxygenation of compound 19 by the Barton reaction yields compound 20 . Compound (I) can be obtained from compound 20 , for example by saponification in the presence of lithium hydroxide or by transesterification, for example with sodium methoxide in methanol. In this method of synthesis, R1, R2, R3, R4 and R5 are as defined above.

According to the invention, the term "evans derivative" is preferably understood to mean a distinct chiral oxazolidin-2-one derivative, such as a 4 (S) -benzyloxazolidin-2-one derivative.

According to the invention, the term "barton reaction" In the case of the synthetic route 2b noted in 2 , it is understood that after the reaction of the hydroxyl group of the compound 19 with phenyl chlorothioinoformate, it means a radical reaction in the presence of tributyltin hydride.

The compounds according to the invention exhibit regulatory properties for receptors of the PPAR type. Activity against PPARα, δ and γ is measured in the transcriptional activity experiment and quantified by the apparent dissolution constant (kdApp), as described in Example 7 below.

In a manner not apparent to the person skilled in the art in view of the prior art, preferred compounds according to the invention exhibit surprising biological activity, in particular binding affinity for PPARδ receptors, which is significantly increased compared to compounds according to patent FR 2 812 876. The KdApp values of the compounds according to the invention for PPARδ receptors are listed in Example 7 and are shown in Table 1 , which values are compared here to those of the compounds of patent application FR 2 812 876: values less than 1 nM And advantageously less than 0.1 nM, i.e., at least 120 times lower than the KdApp value described for the compounds of patent FR 2 812 876, and up to several thousand times lower ( Table 1 ), which is the invention for PPARγ receptors. Reflects a markedly increased affinity of the compound. In Table 1 , KdApp values of any compound of the present invention, as a PPARδ receptor, are listed with some compounds according to the prior art, and compounds exhibiting similar substituents are considered. In particular, the R 1 radical according to the invention is equivalent to the R 10 radical of the compound according to FR 2 812 876 and the R 2 radical according to the invention is equivalent to the R 4 radical of the compound according to FR 2 812 876.

In particular, the compounds according to the invention are modulators of specific receptors of the PPARδ type, ie it represents a ratio of KdApp to PPARγ receptors to PPARα or PPARδ receptors of at least 10. Preferably, the ratio of such PPARα / PPARγ or PPARδ / PPARγ is at least 50 and more advantageously at least 100.

Another subject of the invention is a compound of formula (I) as described above as a medicament.

The compounds according to the invention are particularly suitable for the treatment of:

1) Dermatological conditions related to differentiation and proliferation associated keratinization disorders, in particular vulgar acne, comedonic acne or polymorphic acne, rose acne, nodular cyst acne, acne conglobata, senile acne and secondary Acne, such as the treatment of sun, drug or work acne.

2) other types of keratinization disorders, especially young, ichthyosiform conditions, Darier's disease, palmar keratosis, vitiligo and leukoplakiform conditions, and cutaneous or mucosa Sexual (oral) limbs;

3) other dermatological conditions with inflammatory immunoallergic elements, with or without cell proliferation disorders, in particular all forms of psoriasis of the dermatological, mucosal or nailing state, and psoriasis rheumatism or alternatively skin atopic, such as eczema or respiratory atopy Or gum hyperplasia;

4) all dermal or epidermal proliferation, of benign or malignant, viral or non-viral origin, such as warts, squamous warts and wart epidermal dysplasia, oral or floral papillomatoses and especially T lymphomas, and Proliferation that can be induced by ultraviolet radiation, especially in the case of basal and acute cell epithelial tumors, and any precancerous skin damage such as keratinocytes,

5) other dermatological disorders, such as immune dermatosis, such as erythema lupus, blister immuno and collagen diseases such as sclerosis,

6) dermatological or systemic conditions with immunological factors,

7) skin disorders due to exposure to UV radiation, and recovery or counteracting skin aging that is photoinduced or time aging, or any pathological condition associated with actinic keratosis and pigmentation, or time lapse or photoaging Such as a decrease in dryness,

8) sebaceous dysfunction, such as excessive or simple seborrhea of acne,

9) prevention of cicatrization disorders, or prevention of stretch marks,

10) pigmentation disorders such as hyperpigmentation, blemishes, hypopigmentation or vitiligo,

11) lipid metabolic conditions such as obesity, hyperlipidemia or non-insulin dependent diabetes mellitus,

12) inflammatory conditions such as arthritis,

13) cancer or precancerous condition,

14) prevention of alopecia of various origins, especially alopecia by chemotherapy or radiation,

15) disorders of the immune system such as asthma, type 1 diabetes mellitus, multiple sclerosis or other selective dysfunction of the immune system,

16) Cardiovascular conditions, such as atherosclerosis or high blood pressure.

Subject of the invention is also a pharmaceutical or cosmetic composition which contains, in a physiologically acceptable medium, at least one compound of formula (I) as defined above.

Another subject of the invention is the use of a compound of compound (I) in the treatment of the above-mentioned conditions, in particular in the preparation of a composition for metabolic control and / or recovery of skin lipids.

The composition according to the invention can be administered orally, parenterally, topically or eye. The pharmaceutical composition is preferably packaged in a form suitable for topical application.

By the oral route, the compositions, more particularly pharmaceutical compositions, are sugar-coated tablets, hard gelatin capsules, syrups, suspensions, solutions, powders, granules, emulsions, or vesicles or nanospheres that allow for controlled release. (nanospheres) or polymeric microspheres or in the form of tablets comprising lipids. By parenteral route, the composition may be provided in the form of a solution or suspension for infusion or injection.

The compounds according to the invention are generally administered in one to three doses, in a daily dosage of about 0.001 mg to 100 mg per kg of body weight.

The compounds are generally used systemically at a concentration of 0.001% to 10% by weight, preferably 0.01% to 1% by weight relative to the total weight of the composition.

For the topical route, the pharmaceutical compositions according to the invention are more particularly intended for the treatment of skin and mucous membranes, and are ointments, creams, emulsions, plasters, powders, impregnated pads, solutions, gels, sprays, lotions or It may be in the form of a suspension. It may also be provided in the form of hydrogels and polymeric patches or vesicles or nanospheres or polymeric microspheres or lipids which allow for controlled release. Such topical route compositions may be provided in anhydrous form, aqueous form or emulsion form.

The compounds are used topically at a concentration of generally 0.001% to 10% by weight, preferably 0.01% to 1% by weight relative to the total weight of the composition.

The compounds of formula (I) according to the invention also apply in the field of cosmetics, in particular for systemic and hair hygiene, and more particularly for the regulation and / or recovery of skin lipid metabolism. In comparison with previously known products, these compounds of formula (I) further have the advantage of exhibiting other advantageous properties, in particular anti-inflammatory or soothing properties, which make the compounds less irritating and therefore better tolerated Make it.

Accordingly, another subject of the invention relates to the cosmetic use for systemic or hair hygiene of a composition containing at least one compound of formula (I) in a physiologically acceptable carrier.

Cosmetic compositions according to the invention which contain at least one compound of formula (I) or optical or geometric isomers thereof or salts thereof in a cosmetically acceptable carrier are particularly suitable for creams, emulsions, lotions, gels, lipids or polymeric microspheres. Or in the form of nanospheres or parcels, soaps or shampoos.

The concentration of the compound of formula (I) in the cosmetic composition is from 0.001% to 3% by weight relative to the total weight of the composition.

Compositions as described above may, of course, additionally contain inert additives or pharmacokinetic active additives, or combinations of these additives, specifically the following: wetting agents; Depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; Softeners; Humectants such as glycerol, polyethylene glycol (PEG) 400, thiamorpholinone and derivatives thereof, or urea; Anti-seborrhea or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, salts and derivatives thereof, or benzoyl peroxide; Antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidone; Antibiotic; Keratinoids and in particular β-carotene; Psoriasis inhibitors such as anthraline and derivatives thereof; Eicosa-5,8,11,14-tetranoic acid and eicosa-5,8,11-triinoic acid, and their esters and amides; And finally retinoids. The compounds of formula (I) may also be mixed with vitamin D or derivatives thereof, corticosteroids, free radical resistance agents, α-hydroxy acids or α-keto acids or derivatives thereof, or ion channel blockers.

The compositions also contain flavor improvers, preservatives such as para-hydroxybenzoic acid esters, stabilizers, moisture regulators, pH regulators, osmotic pressure regulators, emulsifiers, UV-A and UV-B blockers, antioxidants such as α-tocopherol, butylated Hydroxyanisole or butylated hydroxytoluene.

Of course, those skilled in the art will carefully select any compound or compounds to be added to the composition such that the advantageous properties inherent in the present invention are not lost or substantially lost by the contemplated addition.

Another subject of the invention relates to a cosmetic method which makes the skin more attractive, characterized in that at least one compound of the formula (I) as defined above is applied to the skin. Control and / or recovery of the metabolism of skin lipids makes it possible to obtain skin with a more attractive surface appearance.

Some examples of the preparation of the active compounds of formula (I) according to the invention, as well as the results of the biological activity of these compounds and various practical formulations based on these compounds will now serve as examples without any restrictive properties.

Example  1: 2 (S)- Ethoxy -3- [3 '-(3- Heptyl -One- Methylureido ) Biphenyl-4-yl] propanoic acid

a) tert-butyl (3-bromophenyl) carbamate

120 g (549 mmol) of di (tert-butyl) dicarbonate are added to 94 g (549 mmol) of 3-bromoaniline and 1 L of dichloromethane in small amounts at ambient temperature. After stirring for 18 hours, the reaction mixture is poured into ice cold water and extracted with dichloromethane. The organic phase is precipitated and separated, dried over magnesium sulphate and evaporated. 138 g of tert-butyl (3-bromobenzyl) carbamate are obtained. Yield = 98%.

b) tert-butyl (3-bromophenyl) -N-methyl-carbamate

19 g (475 mmol) of sodium hydride (60% in oil) is added in small amounts to 114 g (447 mmol) of tert-butyl (3-bromobenzyl) carbamate solution in 800 ml of dimethylformamide. And stir the reaction medium until gas evolution ceases. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring is maintained for 18 hours. The reaction medium is poured into ice cold water and extracted with ethyl acetate. The organic phase is separated by precipitation, dried over magnesium sulfate and evaporated. 115 g of tert-butyl (3-bromobenzyl) -N-methylcarbamate are obtained. Yield = 95%.

c) tert-butyl (4'-formylbiphenyl-3-yl) methyl-carbamate

61.5 g (205 mmol) tert-butyl (3-bromobenzyl) -N-methylcarbamate, 46 g (307 mmol) 4-form of 307 ml (615 mmol) of aqueous potassium carbonate solution (2M) Add dropwise to a mixture of millbenzene-boric acid and 500 ml toluene. The reaction medium is then degassed with argon and 7 g (6.2 mmol) of tetrakis (triphenylphosphine) palladium (0) are added.

After heating to 90 ° C. for 24 h, the reaction medium is poured into water and extracted with ethyl acetate. The organic layer is separated by precipitation, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (70/30). After evaporating the solvent, 67 g of tert-butyl (4'-formylbiphenyl-3-yl) methylcarbamate are collected. Yield = 60%.

d) tert-butyl {4 '-[3- (4 (S) -benzyl-2-oxo-oxazolidin-3-yl) -2 (S) -ethoxy-1 (R) -hydroxy-3 -Oxopropyl] -biphenyl-3-yl} methylcarbamate

72.3 ml (72.3 mmol) of dibutylboron triflate, and then 12.6 ml (72.3 mmol) of diisopropylethylamine are commercially available (S) -4-benzyl-oxazolidine in 150 ml of dichloromethane. From 2-one, see Bernard Hulin et al., J. Med. 15.2 g (57.8 mmol) of (S) -4-benzyl-3- (2-ethoxyacetyl)-cooled to 0 ° C., prepared as described in Chem., 1996,39, 3897-3907. Add dropwise to a solution of oxazolidin-2-one. The reaction medium is stirred at 0 ° C. for 30 minutes and then cooled to -78 ° C. Thereafter, a solution of 15 g (48.2 mmol) of tert-butyl (4'-formylbiphenyl-3-yl) methylcarbamate in 70 ml dichloromethane is added dropwise. After stirring at −78 ° C. to ambient temperature over 4 hours, the reaction medium is cooled to 0 ° C. and a mixture of 130 ml of buffer solution (pH = 7) and 100 ml of methanol is added dropwise, followed by 130 ml hydrogen A mixture of aqueous peroxide solution and 100 ml methanol is added dropwise. The reaction medium is stirred at 0 ° C. for 1 hour and then at ambient temperature for 3 hours. After addition of water, the reaction medium is extracted with dichloromethane. The organic layer is dried over magnesium sulphate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (70/30) and then with a heptane / ethyl acetate mixture with increased polarity up to 50/50. After evaporation of the solvent, 28 g tert-butyl {4 '-[3- (4 (S) -benzyl-2-oxooxazolidin-3-yl) -2 (S) -ethoxy-1 (R) -Hydroxy-3-oxopropyl] biphenyl-3-yl) methylcarbamate was collected. Yield = 81%.

e) tert-butyl (S)-{4 '-[3- (4-benzyl-2-oxo-oxazolidin-3-yl) -2-ethoxy-3-oxopropyl] biphenyl-3-yl } -Methylcarbamate

4.8 ml (9.6 mmol) of sodium bis (trimethyl-silylamide) in 5 g (8.7 mmol) of tert-butyl {4 '-[3- (4, precooled to 0 ° C. in 70 ml of tetrahydrofuran (S) -benzyl-2-oxooxazolidin-3-yl) -2 (S) -ethoxy-1 (R) -hydroxy-3-oxopropyl] biphenyl-3-yl} methylcarbamate Add dropwise to the solution. The reaction medium is stirred at -78 ° C for 1 hour, then 1.3 ml (9.6 mmol) of phenyl chlorothionoformate are added and the medium is stirred at -78 ° C for 1 hour and then at ambient temperature for 1 hour 30 Stir for minutes. After evaporation of tetrahydrofuran, the reaction medium is extracted with dichloromethane and washed with water. The organic phase is separated by precipitation, dried over magnesium sulphate, filtered and evaporated under vacuum. 9 g (8.7 mmol) of the obtained residue was taken up in 100 ml of toluene and 71 mg (0.4 mmol) of 2,2'-azobis (2-methyl-propionitrile), followed by 3.5 ml (13.1 mmol) of Tributyltin hydride is added. The reaction medium is heated at 110 ° C. for 20 minutes. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (90/10) and then with a heptane / ethyl acetate mixture of increased polarity up to 70/30. 2.85 g of tert-butyl (S)-{4 '-[3- (4-benzyl-2-oxooxazolidin-3-yl) -2-ethoxy-3-oxopropyl] ratio after evaporation of the solvent Phenyl-3-yl} methylcarbamate is obtained. Yield = 60%.

f) 4 (S) -benzyl-3- [2 (S) -ethoxy-3- (3 '-(methyl-amino) biphenyl-4-yl) propionyl] oxazolidin-2-one

9 ml (114 mmol) of trifluoroacetic acid in 8.5 g (15.2 mmol) of (S)-{4 '-[3- (4-benzyl-2-oxooxazolidin-3-yl) in 150 ml dichloromethane ) -2-ethoxy-3-oxopropyl] biphenyl-3-yl} methylcarbamate solution is added dropwise. The reaction medium is stirred at ambient temperature for 24 hours, added to water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. 8.7 g of 4 (S) -benzyl-3- [2 (S) -ethoxy-3- (3 '-(methyl-amino) biphenyl-4-yl) propionyl] oxazolidin-2-one Obtained in the form of a trifluoroacetate salt. Yield = 100%.

g) 1- {4 '-[3- (4 (S) -benzyl-2-oxooxazolidin-3-yl) -2 (S) -ethoxy-3-oxopropyl] biphenyl-3-yl ) -3-heptyl-l-methylurea

1.1 ml (7.7 mmol) of triethylamine and then 2.25 ml (14.0 mmol) of heptyl isocyanate were added in 4 g (7.0 mmol) of 4 (S) -benzyl-3- [2 (S)-in 50 ml of dichloromethane. To the solution of ethoxy-3- (3 '-(methylamino) biphenyl-4-yl) propionyl] oxazolidin-2-one is added dropwise. After stirring for 20 hours at ambient temperature, the reaction medium is added to water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (50/50). After evaporation of the solvent, 3.6 g of 1- {4 '-[3- (4 (S) -benzyl-2-oxo-oxazolidin-3-yl) -2 (S) -ethoxy-3-oxopropyl ] Biphenyl-3-yl} -3-heptyl-1-methylurea is collected in the form of a colorless oil. Yield = 86%.

h) 2 (S) -ethoxy-3- (3 '-(3-heptyl-1-methyl-ureido) biphenyl-4-yl] propanoic acid

18 g (9.0 mmol) of 0.5 M aqueous lithium hydroxide solution, 3.6 g (6.0 mmol) of 1- {4 '-[3- (4 (S)), previously cooled to 0 ° C. in 80 ml tetrahydrofuran Benzyl-2-oxooxazolidin-3-yl) -2 (S) -ethoxy-3-oxo-propyl] biphenyl-3-yl} -3-heptyl-1-methylurea solution. The reaction medium is stirred at 0 ° C. for 2 hours, after which a portion of tetrahydrofuran is evaporated and water and n-butanol are added. The reaction medium is oxidized to pH 3 with 1N hydrochloric acid and extracted with n-butanol. The organic phase is dried over magnesium sulphate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (70/30) and then with a heptane / ethyl acetate mixture of increased polarity up to 50/50. After evaporation of the solvent, 1.5 g of 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid are collected in the form of a colorless oil. Yield = 57%.

i) L-arginine salt of 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid

Aqueous solution of 0.4 g (2.3 mmol) of L-arginine was previously heated to 78 ° C. in 22 ml of ethanol in 1 g (2.3 mmol) of 2 (S) -ethoxy-3- [3 '-(3- Heptyl-l-methylureido) biphenyl-4-yl] propanoic acid solution is added dropwise. The reaction medium is heated at 78 ° C. for 1 h, then brought back to ambient temperature overnight and evaporated to dryness in vacuo. The residue obtained is taken up in 15 ml ethyl ether, stirred at ambient temperature for 30 minutes and filtered off. The solid obtained is rinsed with ethyl ether and dried under vacuum in an oven. 1.3 g of L-arginine salt of 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid are obtained in the form of a white powder. Yield = 100%.

Example  2: 2 (S)- Ethoxy -3- [3 '-(1- methyl -3- Pentylureido ) Biphenyl-4-yl] propanoic acid

a) 1- {4 '-[3- (4 (S) -benzyl-2-oxooxazolidin-3-yl) -2 (S) -ethoxy-3-oxopropyl] biphenyl-3-yl } -1-methyl-3-pentylurea

0.8 g (1.4 mmol) of 4 (S) -benzyl-3- [2 (S) -ethoxy-3- (3 '-(methylamino) biphenyl-4-yl) in a similar manner to Example lg) ) Propionyl] oxazolidin-2-one and 0.35 ml (2.8 mmol) of pentyl isocyanate, 0.54 g of 1- {4 '-[3- (4 (S) -benzyl-2-oxooxazolidine- 3-yl) -2 (S) -ethoxy-3-oxopropyl] biphenyl-3-yl} -1-methyl-3-pentylurea is obtained in the form of a colorless oil. Yield = 67%.

b) 2 (S) -ethoxy-3- (3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid

In a similar manner to Example 1h), 0.53 g (0.93 mmol) of 1- {4 '-[3- (4 (S) -benzyl-2-oxo-oxazolidin-3-yl) -2 (S) 0.32 g of 2 (S)-from ethoxy-3-oxopropyl] biphenyl-3-yl} -1-methyl-3-pentylurea and 2.8 ml (1.4 mmol) of an aqueous 0.5N sodium hydroxide solution. Ethoxy-3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] -propanoic acid is obtained in the form of a colorless oil. Yield = 84%.

c) L-arginine salt of 2 (S) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] propanoic acid

0.32 g (0.8 mmol) of 2 (S) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] propanoic acid in a similar manner to Example 1i) And L-arginine salts of 2 (S) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] propanoic acid from 0.13 g (0.8 mmol) of arginine. 0.45 g is obtained in the form of a white solid. Yield = 100%.

Example  3: 2 (S)- Cyclopropylmethoxy -3- [3 '-(3- Heptyl -One- Methylureido ) Biphenyl-4-yl] propanoic acid

a) 3.6 g (12.7 mmol) of tert-butyl (3-bromo-phenyl) -N-methylcarbamate prepared in a similar manner to Example 1b) are dissolved in 15 ml of dichloromethane. 5 ml of trifluoroacetic acid are added and the reaction mixture is stirred at ambient temperature for 1 hour. The reaction is stopped by the addition of 50 ml of saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solution, the residue is chromatographed on silica gel (heptane / ethyl acetate 50/50). 2.14 g of 3-bromo-N-methylaniline are obtained in oil form. Yield = 90%.

b) 890 mg (3.5 mmol) of pinacolborane, 600 in the presence of 130 mg (0.16 mmol, 5 mol%) of palladium dichloride diphenylphosphinopropane ferrocene (PdCl ₂ dppf) in 10 ml dichloroformamide To a mixture of mg (3.2 mmol) 3-bromo-N-methylaniline and 1 g (10.2 mmol) potassium acetate are added. The mixture is stirred at 90 ° C. for 2 hours. The reaction is stopped by the addition of 20 ml of water, followed by extraction with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporation of the solvent, the residue is chromatographed on silica gel (heptane / ethyl acetate 80/20). 420 mg of methyl [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] amine are obtained in oil form. Yield = 57%.

c) 72 ml (0.122 mol, 2.5 eq) of tert-butyl-lithium (1.7M / pentane) 35 g (0.148 mol, 3 eq) in 100 ml of tert-butyl methyl ether at −30 ° C. using a needle Is slowly added to a suspension of 1,4-dibromobenzene. After the mixture is stirred at −30 ° C. for 10 minutes, 5.3 g (0.059 mol) of copper (I) cyanide are introduced into the solution. The reaction mixture is stirred at -30 ° C for 20 minutes. A solution of 5 g (0.049 mol) of methyl (S) -glycidate in 10 ml of tert-butyl methyl ether is added keeping the temperature below -20 ° C. After the mixture is stirred at −30 ° C. for 20 minutes, the reaction is stopped by addition of saturated ammonium chloride solution. The mixture is extracted with 3 x 300 ml of ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporation of the solvent, the residue is chromatographed on silica gel (heptane 100% to heptane / ethyl acetate 60/40). 7.2 g of methyl (S) -3- (4-bromophenyl) -2-hydroxypropionate are obtained in solid form. Yield = 56%.

d) 0.11 ml (1.15 mmol) of bromomethylcyclopropane in 267 mg of diethyl ether, 267 mg (3.48 mmol) of silver oxide and 100 mg (0.38 mmol) of methyl (S) -3- (4 -Bromophenyl) -2-hydroxypropionate is added to the mixture. The reaction mixture is stirred at 50 ° C. for 24 hours. After filtering the mixture, the solvent is evaporated. The residue is chromatographed on silica gel (heptane / ethyl acetate 85/15). 145 mg of methyl (S) -3- (4-bromophenyl) -2- (cyclopropylmethoxy) -propanoate are obtained in the form of an oil. Yield = 50%.

e) 53 mg (0.046 mmol) of tetrakis (triphenyl-phosphine) palladium in 145 mg (0.46 mmol) of methyl (S) -3- (4-bromophenyl)-in 3 ml of dimethylformamide. 2- (cyclo-propylmethoxy) propionate and 129 mg (0.55 mmol) of methyl [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 1) phenyl] amine. 0.3 ml of 2M potassium phosphate solution are added and the reaction mixture is stirred at 90 ° C. for 2 hours. After the reaction is stopped by the addition of 10 ml of water, the extraction is carried out with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporation of the solvent, the residue is chromatographed on silica gel (heptane / ethyl acetate 80/20). 70 mg of methyl (S) -2-cyclopropyl-methoxy-3- [3 '-(methylamino) biphenyl-4-yl] propanoate are obtained in the form of an oil. Yield = 45%.

f) 40 μl (0.25 mmol) of heptyl isocyanate was added to 70 g (0.2 mmol) methyl (S) -2-cyclopropylmethoxy-3- [3 ′-(methylamino) biphenyl- in 2 ml of dichloromethane. 4-yl] -propionate is added to the solution. The reaction mixture is stirred at ambient temperature for 48 hours. After the reaction is stopped by the addition of 2 ml of water, the extraction is carried out with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (heptane / ethyl acetate 70/30). 86 mg of methyl (S) -2-cyclopropyl-methoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] -propanoate are obtained in oil form. . Yield = 87%.

g) 21 mg (0.54 mmol) of sodium hydroxide is dissolved in 2 ml of 9/1 tetrahydrofuran / methanol in 86 mg (0.18 mmol) of methyl (S) -2-cyclopropylmethoxy-3- [ To a solution of 3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propionate. The reaction mixture is stirred overnight at ambient temperature. After the reaction was stopped by the addition of 2 ml water and 0.5 ml acetic acid, the extraction was carried out with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (dichloromethane / methanol 90/10). 70 mg of 2 (S) -cyclo-propylmethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid are obtained in oil form. Yield = 84%.

Example  4: 2- (S)- Propyloxy -3- [3 '-(3- Heptyl -One- Methylureido ) Biphenyl-4-yl] propanoic acid

a) 0.22 ml (2.31 mmol) of propyl iodide, in 3 ml of diethyl ether, 793 mg (3.48 mmol) of silver oxide and 300 mg (1.16 mmol) of methyl (S) -3- (4- To a mixture of bromo-phenyl) -2-hydroxypropionate. The reaction mixture is stirred at 50 ° C. for 12 h. After the mixture is filtered, the solvent is evaporated. The residue is chromatographed on silica gel (heptane / ethyl acetate 80/20). 291 mg of methyl (S) -3- (4-bromophenyl) -2- (propyloxy) propanoate are obtained in the form of an oil. Yield = 83%.

b) 38 mg (0.033 mmol) of tetrakis (triphenyl-phosphine) palladium in 100 mg (0.33 mmol) of methyl (S) -3- (4-bromophenyl) in 1 ml of dimethylformamide -2- (propyl-oxy) propionate and 90 mg (0.39 mmol) of methyl [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -amine. 0.2 ml of 2 M potassium phosphate solution are added and the reaction mixture is stirred at 90 ° C. for 2 hours. The reaction is stopped by the addition of 10 ml of water, after which the extraction is carried out with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporation of the solvent, the residue is chromatographed on silica gel (heptane / ethyl acetate 80/20). 76 mg of methyl (S) -2-propyloxy-3- [3 '-(methylamino) biphenyl-4-yl] propanoate are obtained in oil form. Yield = 70%.

c) 156 μl (0.96 mmol) of heptyl isocyanate in 210 mg (0.64 mmol) of methyl (S) -2-propyloxy-3- [3 ′-(methylamino) biphenyl- in 3 ml of dichloromethane To 4-yl] -propanoate solution. The reaction mixture is stirred at ambient temperature for 48 hours. After the reaction is stopped by the addition of 2 ml of water, the extraction is carried out with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (heptane / ethyl acetate 70/30). 200 mg of methyl (S) -2-propyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoate are obtained in oil form. Yield = 66%.

d) 51 mg (1.28 mmol) of sodium hydroxide in 200 ml (0.42 mmol) of methyl (S) -2-propyloxy-3- [3 'in 2 ml of 9/1 tetrahydrofuran / methanol. To (3-heptyl-1-methylureido) -biphenyl-4-yl] propanoate solution. The reaction mixture is stirred overnight at ambient temperature. The reaction is stopped by addition of 2 ml of water and 0.5 ml of acetic acid and then extraction is performed with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (dichloromethane / methanol 90/10). 147 mg of 2- (S) -propyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid are obtained in oil form. Yield = 76%.

Example  5: 2 (S)- Benzyloxy -3- [3 '-(3- Heptyl -One- Methylureido ) Biphenyl-4-yl] propanoic acid

a) 1.9 ml (16 mmol) of benzyl bromide, in 20 ml diethyl ether, 4.4 g (19 mmol) of silver oxide and 3.5 g (13 mmol) of methyl (S) -3- (4-bromo To a mixture of phenyl) -2-hydroxypropionate. The reaction mixture is stirred at 50 ° C. for 12 h. After filtering the mixture, the solvent is evaporated. The residue is chromatographed on silica gel (heptane / ethyl acetate 80/20). 4 g of methyl (S) -3- (4-bromophenyl) -2-benzyloxypropanoate are obtained in the form of an oil. Yield = 85%.

b) 635 mg (0.55 mmol) of tetrakis (triphenyl-phosphine) palladium in 4 g (11 mmol) of methyl (S) -3- (4-bromophenyl) in 25 ml of dimethylformamide -2-benzyloxy-propionate and 4 g (17 mmol) of methyl [3- (4,4,5,5-tetramethyl-1,3,2-dioxaboloran-2-yl) phenyl] Add to the solution of amine. 10 ml of 2M potassium phosphate solution are added and the reaction mixture is stirred at 70 ° C. for 1 hour. After stopping the reaction with the addition of 50 ml water, the extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulphate. After evaporation of the solvent, the residue is dried over silica gel (heptane / ethyl acetate 80/20) and chromatographed. 2.6 g of methyl (S) -2-benzyloxy-3- [3 '-(methyl-amino) biphenyl-4-yl] propanoate are obtained in the form of an oil. Yield = 61%.

c) 2.25 ml (13.9 mmol) of heptyl isocyanate, 2.6 g (6.95 mmol) of methyl (S) -2-benzyloxy-3- [3 '-(methylamino) biphenyl-4- in 15 ml dichloromethane To the general] -propanoate solution. The reaction mixture is stirred at ambient temperature for 20 hours. The reaction is stopped by the addition of 20 ml of water, followed by extraction with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (heptane / ethyl acetate 70/30). 2.42 g of methyl (S) -2-benzyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoate are obtained in the form of an oil. Yield = 67%.

d) 16 mg (0.4 mmol) of sodium hydroxide in 2 ml of 9/1 tetrahydrofuran / methanol in 70 mg (0.42 mmol) of methyl (S) -2-benzyloxy-3- [3 ' To (3-heptyl-1-methylureido) biphenyl-4-yl] propanoate solution. The reaction mixture is stirred overnight at ambient temperature. The reaction is stopped by addition of 2 ml of water and 0.5 ml of acetic acid and then extraction is performed with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (dichloromethane / methanol 90/10). 49 mg of 2 (S) -benzyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid are obtained in the form of an oil. Yield = 72%.

Example  6: 2 (S)- Allyloxy -3- [3 '-(3- Heptyl -One- Methylureido ) Biphenyl-4-yl] propanoic acid

a) 100 mg of 10% palladium-on-charcoal in 2.4 g (4.66 mmol) of methyl (S) -2-benzyloxy-3- [3 '-(3-heptyl-1-methyl) in 10 ml methanol Ureido) biphenyl-4-yl] propanoate solution. The reaction mixture is stirred overnight under a hydrogen atmosphere. After filtering the reaction mixture, the solvent is evaporated. The residue is filtered over silica gel (ethyl acetate). 1.61 g of methyl (S) -3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] -2-hydroxypropionate are collected in the form of a colorless oil. Yield = 81%.

b) 58 μl (0.70 mmol) of allyl bromide in 162 mg (0.70 mmol) of silver oxide and 200 mg (0.47 mmol) of methyl (S) -3- [3′- in 3 ml of diethyl ether. To (3-heptyl-1-methylureido) biphenyl-4-yl] -2-hydroxy-propanoate. The reaction mixture is stirred at 40 ° C. for 24 hours. After filtering the mixture, the solvent is evaporated. The residue is chromatographed on silica gel (heptane / ethyl acetate 80/20 to 60/40). 180 mg of methyl (S) -2-allyloxy-3- (3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] -propanoate are obtained in oil form. 82%.

c) 56 mg (1.4 mmol, 3 eq) of sodium hydroxide in 200 ml (0.47 mmol, 1 eq) of methyl (S) -2-allyloxy-3 in 2 ml of 9/1 THF / methanol To [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoate solution. The reaction mixture is stirred at ambient temperature for 3 hours. After the reaction is stopped by addition of 2 ml of water and addition of 0.5 ml of acetic acid, the extraction is carried out with ethyl acetate. The organic phases are mixed and dried over sodium sulphate. After evaporating the solvent, the residue is chromatographed on silica gel (dichloromethane / methanol 90/10). 152 mg of 2 (S) -allyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] -propanoic acid are obtained in the form of an oil. Yield = 78%.

Example  7: cross curve ( crossed - curve ) PPAR  Transcriptional Activity Analysis

Activation of receptors by agonists (agonists) in HeLN cells expresses a luciferase reporter gene that generates light in the presence of a substrate. Regulation of PPAR receptors is measured by incubating the cells in the presence of a reference agonist and then quantifying the resulting luminescence. Ligands will replace the agonist at its location. Measurement of this activity is performed by quantifying the light produced. This measurement makes it possible to determine the regulatory activity of the compounds according to the invention by measuring a constant indicating the affinity of the molecule for the PPAR receptor. Since this value may vary depending on basal activity and expression of the receptor, it is called KdApp (KdApp in nM units).

For the determination of this constant, the "cross curve" of the test specimen for the reference agonist was prepared using a 96-well plate: 10 test specimens and concentration 0 were arranged in one row, and 7 concentrations of Argonists and zero concentrations were arranged in a row. This represents 88 measurement points for one product and one receptor. The remaining eight wells were used for repeating controls.

Within each well, cells were treated with one concentration of the test and one concentration of the reference agonist, 2- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido for PPARα. ] Ethyl} phenylsulfanyl) -2-methylpropionic acid, {2-methyl-4- [4-methyl-2- (4-trifluoromethylphenyl) thiazol-5-ylmethylsulfanyl] phenoxy for PPARδ } 5- {4- [2- (methyl (pyrid-2-yl) amino) ethoxy] benzyl} thiazolidine-2,4-dione for acetic acid and PPARγ. Measurements were also made for the whole agonist controls using the same products.

HeLN cell lines used are stable transfectants containing plasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and PPAR (α, δ, γ) Gal-hPPAR. These cells were seeded in 96-well plates at a rate of 10000 cells per well in 100 μl of DMEM medium free of phenol red and supplemented with 10% skim bovine serum. The plates were then incubated at 37 ° C. and 7% CO ₂ for 16 hours.

Various dilutions of test articles and reference ligands were added at a rate of 5 μl per well. The plates were then incubated at 37 ° C. and 7% CO ₂ for 18 hours. This culture medium was inverted and removed, and 100 μl of a 1: 1 PBS / luciferin mixture was added to each well. After 5 minutes, plates were read using a luminescence reader.

These cross curves allow the determination of the AC50 value of the reference ligand (the concentration at which 50% activity is observed) at various concentrations of the test specimen. These AC50 values are calculated using the Schild equation ( " Quantitation in Receptor Pharmacology " Terry P. Kenakin, Receptors and It is used to calculate Schild regression by plotting a straight line corresponding to Channels , 2001, 7, 371-385 ), from which the apparent Kd values (nM) can be obtained.

Transcriptional results:

compound PPARα KdApp (nM) PPARδ KdApp (nM) PPARγ KdApp (nm) Reference 1 : 2- (4- {2- [3- (2,4-Difluorophenyl) -1-heptylureido] ethyl} phenyl-sulfanyl) -2-methyl propionic acid 200 n.a. n.a. Reference 2 : {2-Methyl-4- [4-methyl-2- (4- (trifluoro-methyl) phenyl) triazol-5-ylmethylsulfanyl] -phenoxy} acetic acid n.a. 10 n.a. Reference 3 : 5- {4- [2- (methyl (pyridin-2-yl) amino) ethoxy] benzyl} -thiazolidine-2,4-dione n.a. n.a. 30 Example 1 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propionic acid 30 250 <1 Example 2 : 2 (S) -ethoxy-3- [3 '-(1-methyl-3-phenylureido) biphenyl-4-yl] propionic acid 250 2000 0.03 Example 4 : 2- (S) -propyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propionic acid 30 500 0.025 Example 5 : 2- (S) -benzyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propionic acid 250 n.a. 0.03 Example 6 : 2- (S) -allyloxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propionic acid 2 50 0.003

n.a. Means inactive.

The results indicate the specificity of the affinity of the compounds of the invention for the PPARγ subtype compared to the affinity of the compounds for PPARγ, more particularly for the PPARα subtype or PPARδ subtype.

Example  8: composition

Various practical formulations based on the compounds according to the invention are illustrated in this example.

A- oral route

(a) 0.2 g tablets

Example 1 0.001 g of a compound

0.114 g of starch

0.020 g of dicalcium phosphate

0.020 g of silica

-Lactose 0.030 g

-Talc 0.010 g

0.005 g magnesium stearate

(b) oral suspension in a 5 ml vial

Example 5 0.001 g of a compound

0.500 g of glycerol

0.500 g of 70% sorbitol

Sodium saccharate 0.010 g

0.040 g of methyl para-hydroxybenzoate

-Appropriate amount of flavor

-Appropriate amount for 5 ml of purified water

(c) 0.8 g tablets

Example 2 0.500 g of a compound

0.100 g of pregelatinized starch

0.115 g of microcrystalline cellulose

-Lactose 0.075 g

0.010 g of magnesium stearate

(d) Oral suspension in 10 ml vials

Example 4 0.200 g of compound

-Glycerol 1.000 g

1.000 g of 70% Sorbitol

Sodium saccharate 0.010 g

Methyl para-hydroxybenzoate 0.080.g

-Appropriate amount of flavor

-Appropriate amount for 10 ml of purified water

B- local route

(a) ointment

Example 6 0.020 g of compound

-81.700 g of isopropyl myristate

9.100 g of liquid petroleum jelly

9.180 g of silica ("Aerosil 200" sold by Degussa)

(b) ointment

Example 2 300 g of a compound

-White petrolatum, suitable for 100 g of pharmaceutical

(c) nonionic water-in-oil cream

Example 1 0.100 g of a compound

-A mixture of emulsified lanolin alcohols, waxes and oils ("Anhydrous Eucerin" sold by BDF) 39.900 g

0.075 g of methyl para-hydroxybenzoate

0.075 g of propyl para-hydroxybenzoate

-Suitable amount for 100 g of sterile demineralized water

(d) lotion

Example 3 0.100 g of compound

69.900 g of polyethylene glycol (PEG 400)

30.000 g of 95% ethanol

(e) hydrophobic ointment

Example 5 0.300 g of compound

-Isopropyl myristate 36.400 g

Silicone oil ("Rhodorsil 47 V 300" sold by Rhone-Poulenc) 36.400 g

-Beeswax 13.600 g

-Suitable amount for 100 g of silicone oil ("Abil 300000 cst" sold by Goldschmidt)

(f) nonionic oil-in-water cream

Example 2 1.000 g of compound

-Cetyl alcohol 4.000 g

2.500 g of glyceryl monostearate

2.500 g PEG-50 stearate

Shea butter 9.200 g

2.000 g of propylene glycol

0.075 g of methyl para-hydroxybenzoate

0.075 g of propyl para-hydroxybenzoate

-Suitable amount for 100 g of sterile demineralized water

Claims (26)

Optical and / or geometric, in all ratios of the possible isomers and possible tautomeric forms, as well as compounds of formula (I) and pure or mixtures of compounds of formula (I), and also salts of compounds of formula (I):

[In meals:  R 1 represents an alkyl group having 1 to 6 carbon atoms, an acetyl group, a methylcyclopropane group, an aralkyl group or an aryl group; R2 represents an alkyl group having 3 to 8 carbon atoms; R3 is a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms; R4 and R5, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or a trifluoromethyl radical. A compound according to claim 1, which is provided in the form of an alkali metal salt or alkaline metal salt or organic amine salt. A compound according to claim 2, which is provided in the form of a sodium salt. A compound according to claim 2, which is provided in the form of an amino acid salt. The compound according to claim 4, which is provided in the form of arginine salt or lysine salt. 6. The alkyl radical of claim 1, wherein the alkyl radical of 1 to 6 carbon atoms is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , Isopentyl, n-hexyl, isohhexyl, cyclohexyl, ethylenyl, allyl, propenyl, butenyl, pentenyl or hexenyl radicals. 6. The alkyl radical of claim 1, wherein the alkyl radical of 3 to 8 carbon atoms is n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , Cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, allyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl or octenyl radicals Compound which is characterized in that. The compound according to any one of claims 1 to 5, wherein the halogen atom is a fluorine, bromine or chlorine atom. 6. The aralkyl radical of claim 1, wherein the aralkyl radical is a halogen atom, a CF ₃ radical, an alkyl radical of 1 to 6 carbon atoms, an alkoxy radical of 1 to 6 carbon atoms, unprotected or unsubstituted or 1 to 6 carbon atoms. A benzyl, phenethyl or naphth-2-ylmethyl radical, unsubstituted or substituted with one or more radicals optionally selected from amino or hydroxyl radicals optionally substituted with one or more alkyls of Compound made into. The aryl radical according to any one of claims 1 to 5, wherein the aryl radical is a halogen atom, a CF ₃ radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical having 1 to 6 carbon atoms, a nitro functional group, a polyether radical, an aryl radical, Monosubstituted or substituted with a hydroxyl radical optionally protected with a benzoyl radical, an alkyl ester group, a carboxylic acid, an acetyl or benzoyl group, or an amino functional group optionally protected with an acetyl or benzoyl group or optionally substituted with one or more alkyl of 1 to 6 carbon atoms. A compound which is a phenyl, biphenyl, cinnamil or naphthyl radical which may be substituted. The methoxy, ethoxy, isopropyloxy, tert-butoxy, hexyloxy, according to any one of claims 1 to 5, wherein the alkoxy radical may be optionally substituted with an alkyl radical having 1 to 6 carbon atoms. Benzyloxy or phenoxy radicals. 6. The at least one oxygen atom of claim 1, wherein the polyether radical is a methoxymethoxy, methoxymethylene, ethoxymethoxy, ethoxymethylene or methoxyethoxymethoxy radical. A compound characterized by being a radical having 1 to 6 carbon atoms to be inserted. The compound according to any one of claims 1 to 5, wherein the alkyl ester radical is a carboxylate functional group substituted with an alkyl radical having 1 to 6 carbon atoms. A compound according to claim 1, taken alone or as a mixture, taken from the group consisting of: 1. 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid, 2. 2 (S) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid, 3. 2 (S) -cyclopropylmethoxy-3- [3 '-(3-heptyl-1-methyl-ureido) biphenyl-4-yl] propanoic acid, 4. 2 (S) -propyloxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid, 5. 2 (S) -benzyloxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid, 6. 2 (S) -allyloxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid, 7. 2 (S) -cyclopropylmethoxy-3- [3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid, 8. 3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] -2 (S) -propoxypropanoic acid, 9. 2 (S) -allyloxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid, 10. 2 (S) -benzyloxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid, 11. 2 (S) -methoxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid, 12. 3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] -2 (S) -methoxypropanoic acid, 13. 2 (S) -ethoxy-3- [3 '-(1-methyl-3-propylureido) -biphenyl-4-yl] propanoic acid, 14. 3- [3 '-(3-cyclopropylmethyl-1-methylureido) -biphenyl-4-yl] -2 (S) -ethoxypropanoic acid, 15. 3- [3 '-(3-cyclopentylmethyl-1-methylureido) -biphenyl-4-yl] -2 (S) -ethoxypropanoic acid, 16. 2 (S) -ethoxy-3- [3-fluoro-3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid, 17. 2 (S) -ethoxy-3- [4'-fluoro-3 '-(1-methyl-3-pentyl-ureido) biphenyl-4-yl] propanoic acid, 18. 3- [3,4'-Difluoro-3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] -2 (S) -ethoxypropanoic acid, 19. Methyl 2 (S) -ethoxy-3- [3 '-(3-heptyl-1-methyl-ureido) biphenyl-4-yl] propanoate, 20. Methyl 2 (S) -cyclopropylmethoxy-3- [3 '-(1-methyl-3-pentylureido) biphenyl-4-yl] propanoate, 21. 2 (S) -cyclopropylmethoxy-3- [3 '-(3-cyclopropyl-methyl-1-methylureido) biphenyl-4-yl] propanoic acid, 22. 3- {3 '-[3- (2-cyclohexylethyl) -1-methylureido] -biphenyl-4-yl} -2 (S) -ethoxypropanoic acid, 23. 2 (R) -ethoxy-3- [3 '-(1-methyl-3-pentylureido) -biphenyl-4-yl] propanoic acid, 24. 2 (R) -ethoxy-3- [3 '-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid, 25. 2-ethoxy-3- [3 '-(3-heptyl-1-methylureido) biphenyl-4-yl] propanoic acid, 26. 2 (R) -allyloxy-3 [3 ′-(3-heptyl-1-methylureido) -biphenyl-4-yl] propanoic acid, 27. 3- [3 '-(3-allyl-1-methylureido) biphenyl-4-yl] -2 (S) -ethoxypropanoic acid, 28. Allyl 3- [3 '-(3-allyl-1-methylureido) biphenyl-4-yl] -2 (S) -ethoxypropanoate. 6. A compound according to claim 1, which exhibits at least one of the following properties: R 1 is selected from alkyl radicals selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl radicals, methyl-cyclopropane groups or benzyl radicals, R2 represents an alkyl radical selected from n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptyl radicals, R3 represents a hydrogen atom, R 4 and / or R 5 are selected from hydrogen or fluorine atoms. A cosmetic composition comprising at least one compound as defined in any one of claims 1 to 15 in a physiologically acceptable carrier. A composition according to claim 16, wherein the concentration of the compound (s) according to claim 1 is from 0.001% to 3% by weight relative to the total weight of the composition. Cosmetic use for systemic or hair hygiene of a composition as defined in claim 16. 16. A compound according to any one of claims 1 to 15 as a medicament. Use of a compound according to any one of claims 1 to 15 in the manufacture of a composition for the purpose of regulating and / or restoring skin lipid metabolism. Use of at least one compound according to any one of claims 1 to 15 in the manufacture of a pharmaceutical composition for the purpose of: 1) Dermatological conditions associated with differentiation and proliferation associated keratinization disorders, in particular vulgar acne, comedonic acne or polymorphic acne, rose acne, nodular cystic acne, acne conglobata, senile acne and secondary Acne, such as the treatment of sun, drug or work acne. 2) other types of keratinization disorders, especially young, ichthyosiform conditions, Darier's disease, palmar keratosis, vitiligo and leukoplakiform conditions, and cutaneous or mucosa Sexual (oral) limbs; 3) other dermatological conditions with inflammatory immunoallergic elements, with or without cell proliferation disorders, in particular all forms of psoriasis of the dermatological, mucosal or nailing state, and psoriasis rheumatism or alternatively skin atopic, such as eczema or respiratory atopy Or gum hyperplasia; 4) all dermal or epidermal proliferations of benign or malignant, viral or non-viral origin, such as warts, squamous warts and wart epidermal dysplasia, oral or floral papillomatoses and especially T lymphomas, and Proliferation that can be induced by ultraviolet radiation, especially in the case of basal and acute cell epithelial tumors, and all precancerous skin injuries such as keratinocytes, 5) other dermatological disorders, such as immune dermatosis, such as erythema lupus, blister immuno and collagen diseases such as sclerosis, 6) dermatological or systemic conditions with immunological factors, 7) skin disorders due to exposure to UV radiation, and recovery or counteracting skin aging that is photoinduced or time aging, or any pathological condition associated with actinic keratosis and pigmentation, or time lapse or photoaging Such as dryness, 8) sebaceous dysfunction, such as excessive or simple seborrhea of acne; 9) prevention of cicatrization disorders, or prevention of stretch marks, 10) pigmentation disorders such as hyperpigmentation, blemishes, hypopigmentation or vitiligo, 11) lipid metabolic conditions such as obesity, hyperlipidemia, non-insulin dependent diabetes mellitus, 12) inflammatory conditions such as arthritis, 13) treatment of cancer or precancerous conditions, 14) prevention of alopecia of various origins, especially alopecia by chemotherapy or radiation, 15) disorders of the immune system such as asthma, type 1 diabetes mellitus, multiple sclerosis or other selective dysfunction of the immune system, 16) Cardiovascular conditions, such as atherosclerosis or high blood pressure. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 15 in a physiologically acceptable carrier. The composition according to claim 22, wherein the concentration of the compound (s) according to claim 1 is from 0.001% to 10% by weight relative to the total weight of the composition. The composition according to claim 22, wherein the concentration of the compound (s) according to claim 1 is from 0.01% to 1% by weight relative to the total weight of the composition. Optical and / or geometric, in all proportions of possible isomers, and possible tautomeric forms, or as pure or a mixture of a compound of formula (I) or a compound of formula (I), characterized in that it comprises the following steps: Process for the synthesis of salts of compounds of formula (I): a) from 3-bromoaniline by protecting the amine with di (tert-butyl) dicarbonate and then performing methylation in the presence of sodium hydride Preparation of Compounds of 1 :

[Wherein R5 represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or a trifluoromethyl radical]; b) Preparation of compound 2 by treating compound 1 with acid:

Wherein R 5 is as defined above; c) compound by reaction of pinacolborane with compound 2 in the presence of a catalyst 3 , Manufacturing:

Wherein R 5 is as defined above; d) the following epoxide 4 :

By treating with aryl cuprate 5 , Manufacturing:

[Wherein, R4 represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or a trifluoromethyl radical]; e) Preparation of compound 6 by reacting alkyl halide with compound 5 in the presence of silver oxide:

[Wherein R1 is an alkyl group having 1 to 6 carbon atoms, an acetyl group, a methylcyclopropane group, an aralkyl group or an aryl group, and R4 is as defined above]; f) tetrakis (triphenylphosphine) prepared as by the presence of a palladium Suzuki (Suzuki) coupling the compound 3 with compound 6, according to the reaction of the ring type, Compound 7:

Wherein R 1, R 4 and R 5 are as defined above; g) Preparation of Compound 8 by Reaction of Alkyl Isocyanate with Compound 7 :

[Wherein R2 represents an alkyl group having 3 to 8 carbon atoms, R1, R4 and R5 are as defined above]; h) h1) when R3 is an alkyl radical: by transesterification of the alcohol with compound 8 in the presence of an acid, or h2) when R3 is a hydrogen atom: a compound in the presence of a base By saponification of 8 , Preparation of Compound (I) .

Optical and / or geometric, in all proportions of possible isomers, and possible tautomeric forms, or as pure or a mixture of a compound of formula (I) or a compound of formula (I), characterized in that it comprises the following steps: Process for the synthesis of salts of compounds of formula (I): a) from 3-bromoaniline by protecting the amine with di (tert-butyl) dicarbonate and then performing methylation in the presence of sodium hydride Preparation of Compounds of 1 :

[Wherein, R5 represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or a trifluoromethyl radical]; b) Preparation of compound 2 by treating compound 1 with acid:

Wherein R 5 is as defined above; c) compound by reaction of pinacolborane with compound 2 in the presence of a catalyst 3 , Manufacturing:

Wherein R 5 is as defined above; d) the following epoxide 4 :

Preparation of Compound 5 by treating with aryl halide in the presence of tert-butyllithium and copper cyanide:

[Wherein, R4 represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical having 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or a trifluoromethyl radical]; i) Preparation of Compound 10 by treating Compound 5 with benzyl halide in the presence of silver oxide:

Wherein R 4 is as defined above; j) Preparation of Compound 11 by coupling Compound 3 with Compound 10 by Suzuki type reaction using a palladium catalyst:

Wherein R4 and R5 are as defined above; k) Preparation of Compound 12 by Reaction of Alkyl Isocyanate with Compound 11 :

[Wherein R2, R4 and R5 are as defined in formula (I), where R2 represents an alkyl group having 3 to 8 carbon atoms, and R4 and R5 are as defined above; l) Preparation of Alcohol 13 by Hydrocracking Compound 12 with Hydrogen in the Presence of Palladium-on-Charcoal:

Wherein R 2, R 4 and R 5 are as defined above; m) Preparation of compound 8 by reacting alkyl halide with compound 13 in the presence of silver oxide:

[Wherein, R 1, R 2, R 4 and R 5 are as defined in formula (I), R 1 represents an alkyl group having 1 to 6 carbon atoms, an acetyl group, a methylcyclopropane group, an aralkyl group or an aryl group, and R 2, R 4 And R 5 is as defined above; n) n1) when R3 is an alkyl radical: by transesterification of the alcohol with compound 8 in the presence of an acid, or n2) when R 3 is a hydrogen atom: by saponification of compound 8 in the presence of a base, Preparation of Compound (I) .

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